CRASP-2 proteins of Lyme disease Borrelia

描述（由申请人提供）：莱姆病病原体伯氏疏螺旋体可持续感染人类和其他哺乳动物宿主很长时间。了解莱姆病螺旋体建立和维持慢性感染的机制对于开发长期人类感染的改进治疗方法至关重要。莱姆病螺旋体通常对其宿主的补体激活替代途径具有抗性。对培养细菌的研究发现，两种疏螺旋体外表面蛋白中的任何一种都有助于抵抗宿主补体。这些蛋白质，CRASP-1和CRASP-2（补体调节获得表面蛋白1和2），都结合人补体调节蛋白因子H和FHL-1（因子H样蛋白1），以及其他未鉴定的血清组分。然而，我们发现CRASP-1的产生在哺乳动物感染的最初几天内被抑制，而CRASP-2的产生在哺乳动物感染期间被极大地诱导。因此，CRASP-2是唯一的疏螺旋体蛋白质证明，以促进对宿主补体，在建立哺乳动物感染过程中产生的抗性。我们的研究使我们假设，在哺乳动物感染过程中产生的CRASP-2允许细菌，以避免杀死其宿主的补体激活的替代途径，从而使螺旋体持续感染人类。在本提案中概述了实验，以通过以下方式检验我们的假设：（1）评估哺乳动物感染期间CRASP-2产生的基本性质和精确控制CRASP-2合成的必要性，以及（2）表征CRASP-2表达调节的机制。公共卫生相关性：莱姆病的病原体可以感染人类和其他宿主数年，甚至可能持续个体的一生。我们最近的研究表明，一种名为CRASP-2的疏螺旋体蛋白有助于保护伯氏疏螺旋体免受人类先天免疫系统的杀伤，并且CRASP-2在人类感染期间以高水平产生。我们建议确定莱姆病螺旋体控制CRASP-2合成的机制，长期目标是开发在人类感染期间破坏CRASP-2表达的疗法，从而使细菌对从体内消除敏感。

DESCRIPTION (provided by applicant): The causative agent of Lyme disease, Borrelia burgdorferi, can persistently infect humans and other mammalian hosts for great lengths of time. Understanding the mechanisms by which Lyme disease spirochetes establish and maintain chronic infections will be crucial for developing improved treatments for long-term human infections. Lyme disease spirochetes are generally resistant to their hosts' alternative pathway of complement activation. Studies with cultured bacteria found that either of two borrelial outer surface proteins facilitates resistance to host complement. These proteins, CRASP-1 and CRASP-2 (complement regulator-acquiring surface proteins 1 and 2), both bind the human complement regulatory proteins factor H and FHL-1 (factor H-like protein 1), plus other, unidentified serum components. However, we found production of CRASP-1 is repressed within the first few days of mammalian infection, while CRASP-2 production is greatly induced during mammalian infection. Thus, CRASP-2 is the only borrelial protein demonstrated to facilitate resistance to host complement that is produced during established mammalian infection. Our studies lead us to hypothesize that production of CRASP-2 during mammalian infection permits the bacterium to avoid killing by its host's alternative pathway of complement activation, and thereby enables the spirochete to persistently infect humans. Experiments are outlined in this proposal to test our hypothesis by (1) evaluating the essential nature of CRASP-2 production during mammalian infection and the necessity for precise control of CRASP-2 synthesis, and (2) characterizing mechanisms by which CRASP-2 expression is regulated. PUBLIC HEALTH RELEVANCE: The causative agent of Lyme disease can infect humans and other hosts for years, possibly even for the lifetime of the individual. Our recent studies demonstrated that a borrelial protein named CRASP-2 helps protect Borrelia burgdorferi from killing by the human innate immune system, and that CRASP-2 is produced at high levels during human infection. We propose to determine the mechanisms by which Lyme disease spirochetes control CRASP-2 synthesis, with the long-term goal of developing therapies that will disrupt CRASP-2 expression during human infection and thereby render the bacteria sensitive to elimination from the body.